Delta-9- tetrahydrocannabinol (THC), the primary psychoactive cannabinoid, exerts the majority of its central nervous system effects through interaction with the G-protein linked cannabinoid CB1 receptor. A second cannabinoid-binding seven-transmembrane spanning receptor subtype, termed CB2, has been cloned and appears to be involved with regulation of immunological functions. SR 141716 is the first antagonist of the central cannabinoid receptor CB1 to be identified. It antagonizes the inhibitory effects of cannabinoid receptor agonists on both mouse vas deferens contractions and adenylcyclase activity in rat brain membranes. Availability of a pure cannabinoid receptor antagonist could help substantially in assessing roles of endogenous cannabinoids and blocking their actions. The potential therapeutic utilities of such a compound in modulating the large number of brain systems that appear to express cannabinoid CB1 receptors are especially interesting. Cannabinoid effects on [unreadable]reward[unreadable] systems could be mediated through moderate receptor densities in ventral tegmental area and the nucleus accumbens. To confirm parallelism of effects in humans and animals, the ability of SR141716 to block the acute effects of THC in humans is being assessed for the first time in this phase I clinical trial. In addition, the safety of SR141716 when given alone to light cannabis users, or in combination with THC via inhalation and the pharmacokinetics of SR141716 and THC are being determined. Healthy male subjects with a history of cannabis use receive placebo or active SR141716 prior to smoking placebo or active marijuana. Physiological, biochemical and behavioral measures are being monitored to evaluate pharmacodynamic effects.